Emerging Therapeutic Options for Challenging Medical Targets Surface

In the world of medicine, proteins play a crucial role in nearly every aspect of cell function. This fact has sparked a significant interest in developing treatments that can target proteins, particularly those involved in cancer.

One such investigational drug is Daraxonrasib, developed by Revolution Medicines. Currently in two global Phase III studies, Daraxonrasib is a multi-selective RAS-targeting drug, aiming to combat oncogenic RAS mutations, which are among the most common drivers of human cancers. Revolution Medicines is also developing RAS(ON) inhibitors that target specific G12 mutations.

Physiochemical protein-protein interactions (PPI) drive biological functions, and this understanding has led to the development of innovative treatments. For instance, Circle Pharma has created large molecule macrocycles that target the hydrophobic patch of cyclin proteins, a binding site that hasn't received much attention until now. This approach has demonstrated favorable preclinical in vivo responses.

On the other hand, Gate Bioscience is focusing on toxic secreted protein-type diseases. In a collaboration with the Broad Institute, they are currently working on an orally available molecular gate for Creutzfeldt-Jakob disease (CJD). Gate Bioscience has demonstrated target engagement in vivo for their molecular gate in CJD, and they hope to begin human testing in the next two years.

KRAS, a relatively small protein with no obvious binding pockets, has been challenging to target with small molecules. However, Bayer, in partnership with Kumquat Biosciences, is developing a KRAS-G12D inhibitor for the treatment of cancers with KRAS mutations, particularly pancreatic, lung, and colorectal cancers. Boehringer Ingelheim, in collaboration with Alessio Ciulli's lab at University of Dundee, has discovered a KRAS degrader, ACBI3, that can target a wider range of KRAS-mutated cancers.

Pin Therapeutics has also entered the scene with an orally available, molecular glue degrader, PIN-5018, that selectively targets casein kinase 1 alpha (CK1a) in patients with solid or blood tumors.

Meanwhile, genetic mutations or misfolding of proteins can lead to diseases. To combat this, companies like Revolution Medicines have developed tri-complex inhibitor platforms to target oncogenic RAS mutations. The lead candidate, CID-078, an oral cyclin A/B RxL inhibitor, is more than twice the size of typical small molecule drugs and has shown promising preclinical results.

In addition, an analysis of preliminary safety and activity data from two Phase I studies of daraxonrasib showed promising results in patients with RAS mutant non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC).

These developments in protein-targeting treatments offer hope for those battling cancer and other protein-related diseases. As research continues, we can expect to see more innovative treatments emerging on the horizon.